NM_002878.4(RAD51D):c.26G>C (p.Cys9Ser) AND Breast-ovarian cancer, familial, susceptibility to, 4

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Feb 1, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000231466.25

Allele description [Variation Report for NM_002878.4(RAD51D):c.26G>C (p.Cys9Ser)]

NM_002878.4(RAD51D):c.26G>C (p.Cys9Ser)

Genes:

RAD51D:RAD51 paralog D [Gene - OMIM - HGNC]
RAD51L3-RFFL:RAD51L3-RFFL readthrough [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

17q12

Genomic location:

Preferred name:

NM_002878.4(RAD51D):c.26G>C (p.Cys9Ser)

Other names:

p.C9S:TGC>TCC

HGVS:

NC_000017.11:g.35119588C>G
NG_031858.1:g.5282G>C
NG_054719.1:g.3010C>G
NM_001142571.2:c.26G>C
NM_002878.4:c.26G>CMANE SELECT
NM_133629.3:c.26G>C
NP_001136043.1:p.Cys9Ser
NP_002869.3:p.Cys9Ser
NP_002869.3:p.Cys9Ser
NP_598332.1:p.Cys9Ser
LRG_516t1:c.26G>C
LRG_516:g.5282G>C
LRG_516p1:p.Cys9Ser
NC_000017.10:g.33446607C>G
NM_001142571.1:c.26G>C
NM_002878.3:c.26G>C
NR_037711.2:n.171G>C
NR_037712.2:n.171G>C
p.C9S

Protein change:

C9S

Links:

dbSNP: rs140825795

NCBI 1000 Genomes Browser:

rs140825795

Molecular consequence:

NM_001142571.2:c.26G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002878.4:c.26G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133629.3:c.26G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_037711.2:n.171G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_037712.2:n.171G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Breast-ovarian cancer, familial, susceptibility to, 4
Synonyms:: Breast-ovarian cancer, familial 4
Identifiers:: MONDO: MONDO:0013669; MedGen: C3280345; Orphanet: 145; OMIM: 614291

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000287702	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Feb 1, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000488471	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Jun 9, 2016)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26261251, 21822267, 24130102, 22986143 Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV001434312	Division of Medical Genetics, University of Washington - CSER_CHARM	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 16, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003799801	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Uncertain significance (Oct 21, 2022)	germline	clinical testing	Citation Link,
SCV004017720	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Uncertain significance (Apr 6, 2023)	unknown	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population.

Song H, Dicks E, Ramus SJ, Tyrer JP, Intermaggio MP, Hayward J, Edlund CK, Conti D, Harrington P, Fraser L, Philpott S, Anderson C, Rosenthal A, Gentry-Maharaj A, Bowtell DD, Alsop K, Cicek MS, Cunningham JM, Fridley BL, Alsop J, Jimenez-Linan M, Høgdall E, et al.

J Clin Oncol. 2015 Sep 10;33(26):2901-7. doi: 10.1200/JCO.2015.61.2408. Epub 2015 Aug 10.

PubMed [citation]

PMID:: 26261251
PMCID:: PMC4554751

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000287702.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000488471.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Division of Medical Genetics, University of Washington - CSER_CHARM, SCV001434312.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant has been reported in the literature in individuals with breast and/or ovarian cancer (Wickramanayake 2012, Gutierrez-EnrÃquez 2014, Song 2015). This variant has an allele frequency of 0.0004 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk. PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV003799801.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The RAD51D c.26G>C; p.Cys9Ser variant (rs140825795; ClinVar Variation ID: 127886), has been previously reported in several ovarian cancer cohort (selected references: Wickramanayake 2012 and Song 2015), but in many cases has was also identified in control populations (Weitzel 2019). This variant is found in the general population with an overall allele frequency of 0.04% (113/278,930 alleles) in the Genome Aggregation Database. The cysteine at codon 9 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.218). Based on the available information, the clinical significance of this variant is uncertain References: Song et al. Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population. J Clin Oncol. 2015 Sep 10;33(26):2901-7. PMID: 26261251 Weitzel et al. Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer. Cancer. 2019 Aug 15;125(16):2829-2836. PMID: 31206626 Wickramanayake et al. Loss of function germline mutations in RAD51D in women with ovarian carcinoma. Gynecol Oncol. 2012 Dec;127(3):552-5. PMID: 22986143

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004017720.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

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